1. Field of the Invention
The invention relates to methods of treating autoimmune diseases, e.g., systemic lupus erythematosus and rheumatoid arthritis.
2. Description of the Prior Art
Autoimmunity develops when an organism mounts an anti-self response, usually as a result of abnormalities of the afferent parts of the immune system which are involved in antigen-specific responses. Autoimmunity is a primary cause or secondary contributor in many diseases, usually as a result of the formation of autoantibodies by the immune system of the organism which attack its own cells. Such diseases include, for example, systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hemolytic anemia, and certain forms of progressive liver disease.
Systemic lupus erythematosus produces disturbances in more than one organ system with abnormalities in the immune system. Deposition of antigen-autoantibody complexes in tissues with resultant damage produces many of the clinical manifestations seen in lupus. These include arthritis with pain and swelling in both small and large joints, which may be confused with rheumatoid arthritis. Arthritis or arthralgia is seen in 55 percent of lupus patients. The classic "butterfly rash" which is an erythematous rash over the face and bridge of the nose is seen in 42 percent of lupus patients. Renal involvement secondary to deposition of antigen-antibody complexes producing glomerulonephritis is a major cause of morbidity and mortality in lupus patients. Cardiac involvement is seen in about half the lupus patients and also accounts for significant morbidity and mortality. Systemic lupus erythematosus may involve almost any organ system and confuse the physician as to the primary diagnosis.
Large numbers of autoantibodies which react with the nuclear and cytoplasmic constituents of cells are found in patients with systemic lupus. These antinuclear antibodies (ANA) are detected in 99 percent of lupus patients.
Lupus patients are often initially diagnosed as having rheumatoid arthritis, rheumatic fever, glomerulonephritis, lymphoma, scleroderma or tuberculosis before further evaluation eventually reveals the identity of their disease. The diagnosis of systemic lupus erythematosus can be made if any four or more of the following disorders or blood test results are present at any interval of observation: malar rash, discoid rash, photosensitivity, arthritis, serositis, renal disease, neurological disorder, hematologic disorder, immunologic disorder and high antinuclear antibody titer. E.M. Tan et al., Arthritis Rheum. 25:1271-1277 (1982).
At the present time there is no single effective therapy for systemic lupus. Treatment must be specifically tailored for the organ system or systems affected. Some of the pharmaceutical agents which are currently used include nonsteroidal anti-inflammatory drugs to treat the arthritis associated with lupus; antimalarials, which probably work by direct action on the immune system, to treat the arthritis, skin manifestations and fatigue of lupus; glucocorticoids, used for both their immunosuppressive and anti-inflammatory properties; and immunosuppressive and cytotoxic agents, generally used only when there is significant renal involvement which is unresponsive to glucocorticoids. See D. S. Pisetsky, Advances in Rheumatology, 70(2):337-352 (1986).
All of the currently practiced drug treatments for lupus have significant drawbacks. Apart from gastrointestinal disturbances, the nonsteroidal anti-inflammatory drugs may cause renal toxicity and therefore must be avoided particularly in lupus patients with renal involvement. The antimalarials may cause serious retinopathy which can occur several years after initiation of therapy. Chronic glucocorticoid therapy is associated with a number of pernicious side effects, including hypertension, excessive immunosuppression and CNS dysfunction. Immunosuppressive and cytotoxic agents can cause bone marrow depression and lead to serious infection.
Rheumatoid arthritis in its fully developed form is a symmetrical, inflammatory disease of the synovial lining of peripheral joints which leads to destructive changes. Although arthritis is the most frequent and prominent manifestation, this is a generalized disease involving many body systems.
Pathologically, rheumatoid arthritis is an inflammatory disease involving the immune system. Immune complexes (antigen/antibody) form within the joint and activate the complement system. White blood cells are then attracted into the synovial fluid. These cells phagocytose the immune complexes and in so doing release lysosomal enzymes and other chemical mediators of inflammation. Continued inflammation causes the synovium to proliferate and spread over the joint surface. The thickened synovial tissue, called pannus, releases enzymes which erode both cartilage and bone to cause permanent damage.
Rheumatoid arthritis is treated with many of the same pharmaceutical agents used in systemic lupus. Most patients initially receive nonsteroidal anti-inflammatory drugs, sometimes together with other analgesics. Where the disease is not adequately controlled with these agents, disease-modifying antirheumatic drugs, such as gold salts, D-penicillamine, antimalarial agents and cytotoxic agents, may be utilized. Ultimately, glucocorticoids may be administered, systemically or by the intra-articular route. Continuing therapy with any or all of the aforementioned categories of drugs can produce a variety of well-known adverse effects, and none of these drugs are significantly effective in achieving true remission of the disease in most patients.
It has been hypothesized that many of the manifestations of joint damage occurring in rheumatoid arthritis could be partly, if not largely, the result of damaging free oxygen radicals, large amounts of which are released together with powerful digestive enzymes into the arthritic joint by polymorphonuclear leukocytes undergoing "frustrated phagocytosis". These radicals have been shown to degrade DNA and hyaluronic acid, a major oxygen constituent of synovial fluid, and, to some extent, to degrade also collagen and elastin. Moreover, oxidants can activate latent collagenase, possibly by inactivating protease inhibitors, leading ultimately to cartilage destruction.
It is known that inflammatory cells such as polymorphonuclear leukocytes have opiate receptors. The endogenous opioid .beta.-endorphin has been shown in vitro to stimulate superoxide radical production by human polymorphonuclear leukocytes via an opiate receptor. This superoxide production has been shown to be abolished by equimolar concentrations of the opiate antagonist naloxone. B.M. Sharp et al., J. Pharm. Exp. Ther., 242(2):579-582 (1987). Naloxone has also been shown to inhibit in vitro the production of superoxide from human neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine, which effect is not opiate receptor-mediated, nor is it the result of superoxide scavenging. Simpkins et al., Life Sciences, 37:1381-1386 (1985).
Systemically-administered naloxone has been shown to exert tissue-protective effects in a variety of experimental and clinical conditions in which the damaging effects of superoxide radicals and their derived oxygen species (hydrogen peroxide and the hydroxyl radical) are believed to play a major role. In particular, naloxone has been recently shown to have a protective effect on the ultrastructure of the ischemic canine kidney. H. K. Elkadi et al., J. Surg. Res., 42:675-692 (1987).
Despite the foregoing, neither naloxone nor any other opioid antagonist has been disclosed heretofore as clinically useful in the treatment of the inflammatory manifestations of autoimmune diseases such as systemic lupus and rheumatoid arthritis. There has also been no suggestion that such antagonists might not only relieve inflammation but also reduce autoantibody levels to cause true remission in autoimmune diseases.